1. Field of the Invention
The present invention relates to processes for preparing micronized particles of an anti-muscarinic drug. The present invention also relates to pharmaceutical formulations, preferably dry powder formulations for the prevention and/or treatment of respiratory diseases, which contain such micronized particles, and to methods for the prevention and/or treatment of respiratory diseases.
2. Discussion of the Background
It is known that water soluble quaternary ammonium compounds with antimuscarinic activity tend to irreversibly agglomerate during storage. This is attributed to the formation of crystal bridges between neighbouring particulates due to the absorption of moisture post micronization and subsequent recrystallisation of surface amorphous content which is generated by the high energy micronization process. This problem affects the physical and chemical stability of the drug and its subsequent performance in formulations.
Glycopyrronium is an anti-muscarinic drug commercially available as the bromide salt since many years. Glycopyrronium bromide has two chiral centers corresponding to four isomeric forms comprising 2 pairs of diastereoisomers, namely (3S,2′R)-, (3R,2′S)-, (3R,2′R)-, and (3S,2′S)-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide. Commercially available glycopyrronium bromide consists of the purified “threo” diastereoisomer (3R,2′S) and (3S,2′R) and is hereinafter indicated as rac-glycopyrronium bromide.
However, as other anti-muscarinic agents, glycopyrronium salts have significant stability problems, especially immediately following conventional micronization process by milling.
In fact, glycopyrronium bromide, once micronized, has a strong tendency to irreversibly aggregate and/or agglomerate, which severely hinders downstream drug processing, particularly the preparation of dry powder formulations for administration by inhalation capable of delivering a good respirable fraction.
Various processes have been proposed to process drugs to alter certain physicochemical properties of the drug. However many of those processes involve the use of solvents that have low pharmacological tolerability and therefore their residual presence needs to be strictly monitored. In addition, many of these solvents are highly flammable, making larger scale commercial manufacture difficult. Other known solvent treatment processes, including those using polar solvents, water, or water vapor, tend to cause local solvation processes to occur that subsequently leads to particle growth or irreversible aggregation and agglomeration during drying or storage.
In addition, it is well known that the current state-of-the-art high energy physical processing procedures, such as air jet milling, dry powder ball-milling or high pressure homogenization, result in a partial loss of drug crystallinity. These micronized materials are often subjected to post micronization conditioning; for example, storage under elevated temperature and/or relative humidity in order to condition out any process induced structural disorder and/or amorphous content.
For example, WO 2009/074662, which is incorporated herein by reference in its entirety, discloses the conditioning the post micronized material, such as a glycopyrronium salt, under elevated temperatures (>40° C.) and dry conditions for varying periods of time in order to condition/recrystallize the process induced structural disorder and amorphous content and prevent further irreversible agglomeration occurring on storage. However, exposing the afore-mentioned material to conditions of elevated relative humidity post micronization results in the rapid formation of crystal bridges and irreversible particle agglomeration/crystal growth and therefore this post-micronization elevated temperature conditioning is critical to maintaining a stable product.
Analogously, WO 2009/074666, which is incorporated herein by reference in its entirety, discloses a method for making micronized active particles of water soluble drugs such as a glycopyrronium salt for use in a pharmaceutical composition for pulmonary inhalation that involves high pressure homogenization of said particles in a polar anti-solvent, for instance acetone, ethanol or propan-1-ol, to achieve particle size reduction and subsequent conditioning of the micronized material under dry elevated temperatures to achieve a physically stable powder with respect to agglomeration/aggregation or particle growth.
WO 2005/025536, which is incorporated herein by reference in its entirety, discloses a method for making composite active particles for use in a pharmaceutical composition for pulmonary inhalation that involves jet milling active particles with certain additive materials to maintain stability and enhance fine particle fraction and fine particle dose. Glycopyrronium is cited among other active ingredients. It is anyway difficult and time consuming to eliminate said additives if not needed.
In view of these considerations, it would be highly advantageous to provide a process for preparing micronized particles of a glycopyrronium salt, that are physically stable and do not need further treatments for avoiding the formation of agglomerates. The problem is solved by the process of the present invention.